Cigarette smoking and binge ethanol drinking have been independently associated with a variety of adverse medical consequences. These combined behaviors coexist and are very prevalent in our society. The longterm objective of this revised R21 proposal is to develop an animal model of ethanol binge drinking and cigarette smoke exposure in order to determine if these combined behaviors are more cardiotoxic than either substance alone. It is hypothesized that the combination of nicotine exposure (via cigarette smoke) and binge/bender ethanol consumption will be more cardiotoxic than either substance alone, exemplified by more significant changes in cardiac structure, myocyte histology, hemodynamics and electrocardiogram changes. It is also hypothesized that these adverse effects will be inhibited by carvedilol, a beta-adrenergic blocker. Experiments conducted with carvedilol will be critical for designing mechanistic experiments that would be [unreadable] part of an RO1 application. The aims of this investigation are: 1) To determine in male rats if the combined behaviors of ethanol/cigarette smoke exposure elicit greater changes in left ventricular structure/function and myocyte morphology as assessed by echocardiography and light and electron microscopy, compared to either agent alone; 2) To determine in male rats if the combined behaviors of ethanol/cigarette smoke exposure elicit different or greater hemodynamic changes (increased or decreased blood pressure and heart rate) and cardiac rhythm changes (premature ventricular contractions, atrial and ventricular arrhythmias) compared to either agent alone; 3) To determine if the beta-adrenergic blocker, carvedilol administered prophylactically will provide cardioprotection against the combined effects of ethanol and cigarette smokinginduced cardiac structural and histological changes. A total of 74 animals will be used over the two-year period. The University of Kentucky Tobacco and Health Research Institute smoking exposure system will be used to expose animals to cigarette smoke. Importantly, a radiotelemetry method will be used to measure blood pressure, heart rate and to monitor the electrocardiogram. This allows for these important parameters to be measured in conscious animals. Echocardiography will be used to evaluate cardiac structure. Primary tobacco use and binge alcohol drinking are prevalent in our society, especially among adolescence and young adults. Both behaviors are associated with premature death. Despite the extreme prevalence of these behaviors, how these combined behaviors might adversely affect the structure and function of the heart or even impact long-term health outcomes are unknown. This model will be unique to the field of alcohol research and critical for understanding how these combined behaviors might negatively influence long-term health and/or increase a person's for heart disease or other adverse medical consequences. [unreadable] [unreadable] [unreadable]